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Cell Rep. 2017 Nov 21;21(8):2183-2197. doi: 10.1016/j.celrep.2017.10.083.

GPR56/ADGRG1 Inhibits Mesenchymal Differentiation and Radioresistance in Glioblastoma.

Author information

1
Glioma and Neural Stem Cell Group, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
2
Glioma and Neural Stem Cell Group, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Translational Genomics and Targeted Therapeutics in Solid Tumors Team, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
3
Translational Genomics and Targeted Therapeutics in Solid Tumors Team, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
4
Translational Genomics and Targeted Therapeutics in Solid Tumors Team, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Department of Medical Oncology, Hospital Clinic, Barcelona, Spain.
5
Department of Basic Nursing, Universitat de Barcelona-Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain.
6
Department of Neuro-Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
7
Department of Radiation Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
8
Department of Neurosurgery, Comprehensive Cancer Center, University of Alabama at Birmingham, AL 35233, USA.
9
Department of Translational Molecular Pathology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
10
Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, the Netherlands.
11
Department of Pathology, Hospital Clinic, Barcelona, Spain; Human and Experimental Functional Oncomorphology, IDIBAPS, Barcelona, Spain.
12
Department of Radiology, Hospital Clinic, Barcelona, Spain.
13
Department of Radiation Oncology, Hospital Clinic, Barcelona, Spain.
14
Stem Cells and Aging Unit, Biomedicine Institute of València (IBV), Spanish National Research Council (CSIC), València, Spain.
15
Department of Pediatrics, University Hospital of Navarra, Pamplona, Navarra, Spain; The Health Research Institute of Navarra (IDISNA), Pamplona, Spain; Program in Solid Tumors and Biomarkers, Foundation for Applied Medical Research (CIMA), Pamplona, Spain.
16
Clinical and Experimental Neuroimmunology, IDIBAPS, Barcelona, Spain.
17
Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
18
Glioma and Neural Stem Cell Group, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Translational Genomics and Targeted Therapeutics in Solid Tumors Team, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Department of Medical Oncology, Hospital Clinic, Barcelona, Spain.
19
Glioma and Neural Stem Cell Group, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Translational Genomics and Targeted Therapeutics in Solid Tumors Team, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain. Electronic address: niglesia@clinic.cat.

Abstract

A mesenchymal transition occurs both during the natural evolution of glioblastoma (GBM) and in response to therapy. Here, we report that the adhesion G-protein-coupled receptor, GPR56/ADGRG1, inhibits GBM mesenchymal differentiation and radioresistance. GPR56 is enriched in proneural and classical GBMs and is lost during their transition toward a mesenchymal subtype. GPR56 loss of function promotes mesenchymal differentiation and radioresistance of glioma initiating cells both in vitro and in vivo. Accordingly, a low GPR56-associated signature is prognostic of a poor outcome in GBM patients even within non-G-CIMP GBMs. Mechanistically, we reveal GPR56 as an inhibitor of the nuclear factor kappa B (NF-κB) signaling pathway, thereby providing the rationale by which this receptor prevents mesenchymal differentiation and radioresistance. A pan-cancer analysis suggests that GPR56 might be an inhibitor of the mesenchymal transition across multiple tumor types beyond GBM.

KEYWORDS:

GPR56; NF-κB; glioblastoma; glioma stem-like initiating cell; mesenchymal differentiation; radioresistance; tumor plasticity

PMID:
29166609
DOI:
10.1016/j.celrep.2017.10.083
[Indexed for MEDLINE]
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